Stimuli-Responsive Polymeric Microneedles for Transdermal Drug Delivery

Yonghang Chen; Xinfang Li; Weijiang Yu; Youxiang Wang

doi:10.7536/PC200755

Progress in Chemistry ›› 2021, Vol. 33 ›› Issue (7) : 1152-1158 DOI: 10.7536/PC200755

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Stimuli-Responsive Polymeric Microneedles for Transdermal Drug Delivery

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Abstract

The polymeric microneedles, which has excellent mechanical property and biocompatibility, can pierce the stratum corneum in a minimally-invasive manner and result in efficient transdermal delivery of drugs. Thereby the polymeric microneedles can effectively treat various diseases, such as diabetes, cancer, obesity, eye diseases and so on. How to control the release behavior of the loaded drug is the key point in the polymeric microneedles. Stimuli-responsive polymeric microneedles, as an emerging technology for on-demand drug delivery, can achieve topical accurate release of drugs according to the change of the external environment or the physiological signal in cutaneous environment, making it the current research hotspot in transdermal drug delivery. At present, stimuli-responsive polymeric microneedles are always designed based on light response, pH response, enzyme response and glucose response. This paper reviews the recent researches of the stimuli-responsive polymeric microneedles in detail. Challenges and prospects of stimuli-responsive polymeric microneedles are also discussed.

Contents

1 Introduction

2 Types of drug-loaded polymeric microneedles

3 Applications of stimuli-responsive polymeric microneedles in transdermal drug delivery system

3.1 Tumor treatment

3.2 Diabetes treatment

3.3 Obesity treatment

3.4 Treatment of other diseases

4 Conclusion and outlook

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Keywords

polymeric microneedles / transdermal drug delivery / stimuli-responsive / diseases treatment

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Yonghang Chen, Xinfang Li, Weijiang Yu, Youxiang Wang. Stimuli-Responsive Polymeric Microneedles for Transdermal Drug Delivery. Progress in Chemistry, 2021, 33(7): 1152-1158 DOI:10.7536/PC200755

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1 Introduction

Transdermal administration refers to the transdermal absorption of drugs to achieve local or systemic treatment. Compared with oral and subcutaneous drugs, transdermal drug delivery systems can deliver drugs in a painless manner and avoid the first-pass effect of the liver. However, the outermost layer of the skin is the lipophilic dense stratum corneum, which limits the transdermal delivery efficiency of most hydrophilic drugs and macromolecular drugs^[1,2]. In order to solve this problem, researchers have used chemical penetration enhancers, iontophoresis, electroporation, ultrasonic conduction, microneedles and other physical or chemical methods to promote the transdermal absorption of drugs^{[3⇓⇓⇓~7]}. Among them, microneedles, as a safe, efficient and painless new transdermal drug delivery method, have attracted wide attention.

Microneedles are arrays of micron-sized needles that mediate the local delivery of drugs^[8]. The microneedles can pierce the stratum corneum of the skin and produce reversible microchannels on the skin to promote the smooth passage of drugs through the microchannels to the capillaries of the dermis, thus achieving the effect of local or systemic treatment. The materials for preparing the microneedles are gradually expanded from silicon and metal to polymer materials. Silicon is the first material used to prepare microneedles, but the cost of silicon microneedles is high, the manufacturing process is complex, and the needle body may break in the skin. Metal microneedles have excellent mechanical properties, but the drug loading is limited, so these two kinds of microneedles are not widely used in biological applications. Polymer microneedles have become a research hotspot in the field of microneedles due to their excellent biocompatibility^[9]. At present, the main preparation methods of polymer microneedles include micro-molding, drawing lithography, droplet-bornair blowing, electro-drawing and 3D printing^[10,11]. Polymer drug-loaded microneedles can conveniently control the release behavior of drugs through the selection of polymer materials, which makes them become the focus of attention in this field.

2 Types of polymer drug-loaded microneedles

According to the difference of drug release behavior, polymer microneedles can be divided into three types: sustained release microneedles, rapid release microneedls and stimulus-responsive release miconeedles.

Biodegradable polymer materials, such as polylactic acid (PLA), poly (lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL) and chitosan (CS), are often used to prepare drug delivery microneedles^{[12⇓⇓~15]}. When the microneedle is inserted into the skin, the drug will be released slowly with the degradation of the polymer, thus maintaining a stable blood concentration and reducing the frequency of drug administration. Rapid drug release microneedles are usually made of polymer materials that can be dissolved quickly, such as hyaluronic acid (HA), polyvinylpyrrolidone (PVP), poly-L-glutamic acid (γ-PGA), starch and other materials. When the microneedles are inserted into the skin, they absorb tissue fluid and dissolve to release drugs quickly^{[16⇓⇓~19]}. At present, the research of drug sustained-release microneedles and drug rapid-release microneedles has been very mature. However, it is of great significance to control the release of drugs loaded in microneedles according to biological signals related to pathological processes or external stimuli, so as to improve the specificity of drug delivery, which is also the core element of transdermal drug delivery with microneedles.

The research of stimulus-responsive drug delivery system, especially the design of stimulus-responsive nanoparticles, has a long history, and its research results provide a good inspiration for the stimulus-responsive release of polymer drug-loaded microneedles. The stimulus-responsive drug delivery system can release drugs at the target site according to the difference between the microenvironment of the target tissue and the normal tissue of the human body or by applying external stimuli, thereby effectively improving the specificity of drug delivery and reducing toxic and side effects^{[20⇓⇓~23]}. Inspired by this, in the transdermal delivery design of polymer drug-loaded microneedles, people use the difference of skin biological signals (such as pH value), the difference of biological signals related to pathological processes (such as glucose concentration of diabetic patients) or the external stimuli (light, magnetism, etc.) Applied on the skin surface.To realize the on-demand administration of small molecular drugs and biological macromolecular drugs loaded in polymer microneedles, which can greatly improve the treatment efficiency and reduce toxic and side effects^[24]. At present, the research of stimuli-responsive polymer microneedles mainly focuses on light response, pH response, enzyme response and glucose response. In this paper, we will review the research progress of stimuli-responsive polymer microneedles in detail from the application of microneedles in different diseases, and look forward to the future development of this field.

3 Application of stimuli-responsive polymer microneedles in transdermal drug delivery

3.1 Tumor therapy

Cancer is one of the most serious diseases threatening human health^[25,26]. Conventional cancer treatment methods, such as drug chemotherapy, often require multiple intravenous injections, which cause intense pain to patients and may cause serious side effects^[27]. Transdermal delivery of stimulus-responsive polymer microneedles can use exogenous or endogenous signals to better control the time and space of drugs, improve patient compliance, improve drug delivery efficiency and reduce side effects.

In the treatment of cancer, immunotherapy is a wide range of anti-cancer therapies that use the human immune system to treat cancer, which can enhance the specific and lasting anti-cancer response. Cancer vaccines and immune checkpoint blockade have made remarkable achievements in clinical treatment^[28,29]. Because there are a large number of immature dendritic cells (DCs) in the epidermis and dermis of human skin, which can ingest, process and present antigens, and bring them to the immunoreactive areas of lymph nodes, they are ideal targets for triggering strong immune responses to tumor antigens. Therefore, transdermal delivery based on microneedles offers the possibility of immunotherapy of tumors^[30]. Compared with subcutaneous intramuscular injection, microneedle-mediated cancer vaccine delivery can produce stronger local immunity^[31].

The pH value of skin epidermis is about 5. 5. Using the weak acidity of skin epidermis as a stimulus signal to prepare pH-responsive microneedles provides a good means for the regulation of drug transdermal release behavior^[32,33]. Duong et al. prepared a pH-responsive coated microneedle for delivery of a DNA vaccine^[34]. The pH-responsive multilayer polyelectrolyte is coated on the surface of the polycarbonate microneedle by a layer-by-layer self-assembly technique. The multilayer polyelectrolyte is composed of two parts: an inner layer of a pH-responsive charge inversion polycation/negatively charged immunostimulatory adjuvant poly (I: C) and a vaccine-loaded outer layer of a DNA vaccine/polyethyleneimine-deoxycholic acid. When the microneedles are inserted into the skin, the local acidic environment of the epidermis promotes the polycation in the transition layer to convert into polyanion copolymer, which releases DNA vaccine and poly (I: C) due to electrostatic repulsion. Melanoma model experiments in mice showed that the pH-responsive microneedles could maintain the activity of adjuvant and vaccine for a long time, and the immune response was stronger than that of subcutaneous vaccine.

On the other hand, Gu et al. prepared a hyaluronidase stimulation-responsive hyaluronic acid microneedle in the treatment of tumor by blocking the immune checkpoint^[35]. Hyaluronidase is overexpressed in various types of cancer cells and has been recognized as a tumor marker. They first prepared 1-methyl-DL-tryptophan (1-MT) modified hyaluronic acid, which self-assembled to form nanoparticles and encapsulated programmed death factor-1 antibody (aPD1), and then loaded them into hyaluronic acid microneedles. In the tumor area, the high concentration of hyaluronidase will enzymatically react with hyaluronic acid, destroy the amphiphilic structure of nanoparticles, and promote the release of aPD1 in nanoparticles, while 1-MT is an inhibitor of immunosuppressive enzyme IDO, which is helpful to enhance the effect of immunotherapy. Wang et al. Used glucose in the human body as a physiological signal to prepare hyaluronic acid microneedles loaded with pH-responsive dextran nanoparticles (NPs) of glucose oxidase and aPD-1^[36]. To sum up, microneedles can deliver vaccines and antibodies to the epidermis and dermis with immune function by piercing the stratum corneum in a painless way, thus improving the compliance of patients. At the same time, microneedles are beneficial to maintain the activity of adjuvant and vaccine for a long time, and the immune response produced by microneedles is stronger than that of subcutaneous vaccine, showing excellent clinical application potential.

In addition, microneedles also have broad application prospects in the delivery of genes and chemotherapy drugs for the treatment of subcutaneous tumors. Wang et al. prepared a skin microenvironment responsive coated microneedle for gene therapy of skin cancer^[37]. As shown in fig. 1, the pH-responsive multilayer polyelectrolyte is coated on the surface of the polycaprolactone microneedle by a layer-by-layer self-assembly technique. The multilayer polyelectrolyte is composed of two parts: a transition layer of polylysine modified by dimethylmaleic anhydride (PLL-DMA)/polyethyleneimine and a gene loading layer of p53 therapeutic gene/polyethyleneimine. Among them, PLL-DMA can achieve charge reversal in acidic skin environment, destroy the transition layer structure and promote the rapid release of p53 gene. In vivo experiments showed that the tumor inhibition efficiency of tr-MNP was 90. 1%, while the tumor inhibition efficiency of ntr-MNP was only 46. 4% and 30. 5%.

Near-infrared light has strong penetrability to human tissues and little damage to tissues, and can be combined with photosensitizers or photothermal therapeutic agents to locally target and efficiently treat tumors. Chen et al. prepared a microneedle system with near-infrared light stimulation response, which can provide photothermal therapy and chemotherapy for tumors at the same time, play a synergistic therapeutic effect, and retain the needle tip under the skin to achieve multiple controllable drug delivery^[38]. The tip of the microneedle system is composed of polycaprolactone (PCL) containing lanthanum hexaboride (LaB₆) nanoparticles and doxorubicin (DOX), and the support structure is composed of polyvinyl alcohol/polyvinylpyrrolidone (PVA/PVP). Because the PCL has the properties of high hydrophobicity and thermal fusion, the microneedle does not release drugs without the irradiation of near-infrared light, and the LaB₆ nanoparticles generate heat when stimulated by external near-infrared light,The system can not only realize the controlled release of chemotherapeutic drugs on time and on demand, but also realize the synergistic treatment of photothermal therapy and small molecule drug chemotherapy. In vivo experiments in mice showed that the microneedle-mediated synergistic therapy completely eradicated 4 T1 tumors within one week after one application and three laser treatment cycles, and the tumors did not recur, showing a good therapeutic effect. The medicine is released through the near infrared light stimulation response, the operation is simple and convenient, the time and space are controllable, and the medicine can be administered or interrupted at any time, thereby providing great convenience for personalized treatment.

3.2 Diabetes treatment

Diabetes is one of the most serious global diseases. Patients with type I diabetes need insulin to maintain normal blood sugar. Patients with type 2 diabetes mellitus can maintain normal blood sugar through daily exercise and dietary adjustment, while patients with severe type 2 diabetes mellitus need to inject insulin or anti-diabetic drugs glucagon-like peptide-1 (GLP-1) and its analogues^[39⇓~41]. However, the traditional intraperitoneal injection of insulin can cause intense pain to patients and can not achieve accurate blood sugar control^[42]. Therefore, the intelligent control of drug release according to the fluctuation of blood glucose level is considered to be an ideal treatment for type I and advanced type II diabetes mellitus^[43]. Glucose-responsive polymer microneedles effectively regulate the blood glucose level of patients by detecting glucose concentration in real time and delivering drugs in a painless and timely manner^{[44⇓⇓⇓⇓⇓~50]}.

At present, glucose oxidase (GOx) is mainly used as the glucose sensor in the glucose-responsive microneedle system. Glucose oxidase can catalyze the oxidation of glucose to ${(glucose}+\mathrm{O}_{2}+\mathrm{H}_{2}\mathrm{O}\stackrel{\mathrm{GOx}}{\longrightarrow}\text{gulconicacid}+\mathrm{H}_{2}\mathrm{O}_{2})$, thus forming a hypoxic, acidic and H₂O₂ rich local environment, which can serve as a biological signal to trigger the release of drugs^[39].

Gu Zhen and others have carried out a series of studies in this field. They conceived the concept of "intelligent insulin microneedle patch" and prepared the microneedle that uses hypoxia environment as a biological signal to regulate insulin release for the first time^[44]. They first prepared glucose-responsive nanovesicles (GRV) embedded with insulin and glucose oxidase, and then loaded them into hyaluronic acid microneedles. Glucose-responsive nanovesicles (GRV) are formed by self-assembly of hyaluronic acid modified by hypoxia-responsive hydrophobic groups (2-nitroimidazole).When local hypoxia occurs, the hydrophobic 2-nitroimidazole group can be reduced to the hydrophilic 2-aminoimidazole group, which destroys the amphiphilic structure of GRV vesicles and promotes the release of insulin encapsulated in GRV vesicles.

Glucose oxidase catalyzes the oxidation of glucose to produce H₂O₂, and H₂O₂ can lead to inflammation. In order to solve this problem, Gu Zhen et al prepared a hyaluronic acid microneedle with hypoxia and H₂O₂ response^[45]. As shown in fig. 2, 2-nitroimidazole is covalently bound to the polyserine segment in the copolymer via a thioether bond. With the increase of glucose content in vivo, glucose will enter the vesicle through diffusion, and under the action of glucose oxidase, a local environment with hypoxia and rich H₂O₂ will be produced, and the 2-nitroimidazole group will be reduced to hydrophilic 2-aminoimidazole, which will destroy the amphiphilic structure of the vesicle and promote the release of insulin encapsulated in the vesicle. At the same time, the thioether of the H₂O₂ response is converted into a sulfone group, and the H₂O₂ is consumed. The diabetic mouse model experiment shows that the microneedle system can strictly control the blood glucose concentration of the mouse, greatly reduce the inflammatory reaction caused by the H₂O₂, and effectively increase the biocompatibility of the microneedle system. It is worth mentioning that once the normal blood sugar concentration is reached, the microneedle system will inhibit insulin release, thus effectively reducing the complications caused by hypoglycemia.

Catalase can catalyze the decomposition of H₂O₂, and the introduction of catalase into the microneedle system can also remove the H₂O₂ produced in the glucose reaction catalyzed by glucose oxidase. Gu Zhen et al. Prepared a kind of polyvinyl alcohol (PVA) crosslinked microneedles with core-shell structure by multi-casting method^[46]. The shell part of the microneedle contains catalase, which is designed to remove excess H₂O₂ generated in the system and improve biocompatibility.

Chen et al. Developed a pH-responsive microneedle patch for the delivery of Exendin-4 (Ex4), a drug used in the clinical treatment of type 2 diabetes, using the decrease in pH caused by the enzymatic oxygen reaction of glucose oxidase^[47]. In order to achieve on-demand delivery of Ex4, Ex4 is loaded in calcium phosphate mineralized particles (m-Ex4), which can spontaneously degrade and release drug in a low pH environment. Glucose oxidase (GOx) loaded on the mineralized particles of copper phosphate (m-GOx) can regulate the pH value of the local environment according to the blood glucose concentration. M-GOx and m-Ex4 are integrated into an alginate-based microneedle array. Under hyperglycemic conditions, m-GOx converts glucose signals into H⁺ signals that trigger the dissociation of m-Ex4 particles, thereby releasing Ex4.

In the latest study, Chen et al. Used phenylboronic acid as a glucose-responsive element to prepare an "enzyme-free" semi-interpenetrating hydrogel microneedle to avoid the influence of the H₂O₂ of the enzymatic reaction product of glucose oxidase^[48].

However, smart insulin microneedles still have some challenges, such as the feasibility of large-scale manufacturing design and insulin loading. In view of this, Gu Zhen and others have developed a new generation of intelligent insulin patches^[49]. The insulin patch is only the size of a coin (5 cm²), is easy to manufacture industrially, and can achieve clinically relevant dosage requirements and rapid insulin release, and the time for regulating glucose release can be more than 20 hours. The microneedles use phenylboronic acid as a glucose-responsive component, a mixture of insulin, monomer and crosslinker is poured into a mold, and then the microneedle matrix is formed by a very convenient in-situ photopolymerization method. When exposed to hyperglycemic conditions, the negative charge in the polymer matrix increases, thus weakening the electrostatic interaction between the negatively charged insulin and the polymer, causing a volume change in the polymer matrix, thereby promoting rapid diffusion of insulin; Under normal blood sugar conditions, the electrostatic interaction is restored, which can slow down the release rate of insulin and reduce the risk of hypoglycemia. In vivo experiments in mice and minipigs have shown that microneedle patches can regulate glucose levels within a target range, and that different sizes of patches can be used to adjust insulin doses to alter each person's ability to respond to glucose challenge for clinically personalized treatment.

Traditional microneedle arrays used for insulin delivery lack the ability to detect glucose concentration, so it is necessary to frequently detect the glucose concentration in the blood in order to apply microneedles to deliver insulin to maintain a normal blood sugar situation. The inability to achieve precise glycemic control increases the risk of diabetic complications. Glucose-responsive polymer microneedles intelligently control insulin release according to the fluctuation of the patient's blood sugar level, which can strictly control the patient's blood sugar level within the normal range.

3.3 Obesity

Obesity affects people's clothing, food, housing, transportation and quality of life, and obese patients can cause a series of diseases, such as diabetes, hyperlipidemia and hypertension. Excess white adipose tissue (WAT) is a major cause of obesity^[51]. In the study of transdermal drug delivery mediated by microneedles for the treatment of obesity, the researchers prepared hyaluronic acid microneedles loaded with caffeine or β3-adrenoceptor agonist, respectively, and both microneelles led to significant weight loss in obese mice induced by high-fat diet, which provided the possibility of transdermal treatment of obesity^[52,53]. Zhang et al. Used glucose as a physiological signal to prepare a hyaluronic acid microneedle system loaded with rosiglitazone, in which glucose oxidase (GOx) and catalase (CAT) were loaded^[54]. When GOx converts glucose into gluconic acid, it produces a local acidic environment, and the pH-responsive dextran nanoparticles then release rosiglitazone, which promotes the conversion of white adipose tissue to brown adipose tissue, and CAT is used to consume excess hydrogen peroxide produced during the enzymatic reaction. Animal experiments show that the microneedle system can effectively control the weight of obese mice.

3.4 Other diseases

In addition to the treatment of cancer, diabetes and obesity, stimulus-responsive polymer microneedles are also used in the treatment of many other diseases. Zhang et al. prepared a thrombin stimulation-responsive microneedle system^[55]. Thrombin, a serine protease similar to trypsin, plays a crucial role in the clotting system. They grafted heparin to hyaluronic acid through thrombin cleavage peptide, and prepared crosslinked hyaluronic acid microneedles with sustained anticoagulant regulation as a substrate. When the concentration of thrombin increases, heparin is rapidly released, thereby preventing thrombin from triggering the formation of blood clots. Subsequent in vivo animal experiments showed that the patch could prevent abnormal coagulation and acute pulmonary thrombosis for a long time.

Wang et al. prepared chitosan microneedle patches to treat wound healing^[56]. The temperature-sensitive pNIPAM hydrogel loaded with vascular endothelial growth factor (VEGF) is integrated into the microporous structure of the microneedle to realize the intelligent and controllable release of the drug through the temperature rise caused by the inflammatory reaction at the wound site, and at the same time, the microneedle can promote wound healing due to the combination of the natural antibacterial property of chitosan.

4 Conclusion and prospect

Stimulus-responsive polymer microneedles have developed rapidly, not only in the updating of preparation materials, but also in the continuous expansion of application fields.

In the latest study, researchers have used a combination of microneedles and various materials to achieve oral delivery of biomacromolecules such as proteins. A self-orienting millimeter-scale applicator (SOMA) was developed by Traverso and Langer of Massachusetts Institute of Technology (MIT), and insulin was administered orally^[57]. The device is inspired by the self-orienting leopard tortoise, which can roll over while on its back. As shown in Figure 3, SOMA can be automatically positioned after oral administration into the body. When it passes through the gastrointestinal tract, the sugar disk in the built-in power source dissolves quickly, the compression spring releases elastic potential energy, and the drug-loaded microneedles connected to it can pierce the gastric mucosa in the same direction and release drugs each time.

Similarly, they developed a new type of internal stress-mediated oral drug capsule called the luminal unfolding microneedle injector (LUMI)^[58]. The pH-sensitive methacrylic acid-ethyl acrylate copolymer enables the capsule to exist stably in a gastric acid environment (pH = 1.5 to 3.5), and when the pH-sensitive methacrylic acid-ethyl acrylate copolymer reaches the small intestine, the pH value gradually increases to about 6, the polymer is dissolved, and the elastic potential energy of the compression spring is released, so that the three arms of the LUMI are extended. Each degradable arm of LUMI contains drug-loaded microneedles, and when the arm is opened, its release force causes the microneedles to pierce the small intestinal wall and release the drug. In addition, they also prepared a temperature-responsive "flower-like" microneedle integrated device for gastrointestinal drug delivery^[59]. The microneedle system combine a deformable structural material and a thermally responsive element and has a wide range of applications in that gastrointestinal tract.

At present, great progress has been made in the field of polymer microneedle transdermal drug delivery, and new polymer materials and manufacturing technologies emerge in endlessly. The microneedles can not only deliver drugs on demand through stimulation response, but also be customized to improve the quality of life of patients and achieve better therapeutic effects. However, the biomedical application of microneedles is still in its infancy, and how to achieve large-scale industrial manufacture of microneedles and ensure the precise regulation of the activity and drug loading of biological drugs is an important issue facing us at present. With the further research, microneedles can be combined with some cutting-edge technologies, such as diagnostic and therapeutic integrated microneedle system, wearable microneedle system and microneelle integrated system, which will become a hot spot in the field of microneelle research.

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